Our primary overall goal is to identify specific genetic variants that contribute to the formation and rupture of intracranial aneurysms (IA). Both linkage analysis and genome-wide association studies (GWAS) have identified potentially interesting gene regions. However, no causal gene variants for IA have been identified by any study to this point. A more effective strategy to detect causal gene variants and relevant gene pathways may be to focus on the most densely affected families, which are likely to have the strongest genetic contribution to disease risk. The Primary Aims of This Pilot Sequencing Study are: 1) To use whole exome sequencing to identify novel, rare genetic variants in 7 extended multiplex families with a strong familial aggregation of intracranial aneurysms. 2) To screen the newly identified variant(s) for segregation with IA among affected individuals in the same family and absence in control populations. We propose to sequence 4-5 affected family members in each of these 7 families. Identification of potentially relevant variants will include a highly detailed and iterative process involving identification of nonsynonymous and synonymous SNPs as well as insertion/deletions, validation of variants, and prioritization of potential variants including their probable effect on gene function. Subsequently, we determine the frequency of identified novel, rare and functionally relevant variants detected in these 7 families among 500+ additional FIA families. Study collaborators will examine expression of identified genes in aneurysmal and normal arterial tissue. Our research team has worked together for nearly a decade in the study of the genetics of IA, have experience with exome sequencing studies, and have collaborated with CIDR in a number of past and ongoing projects including a linkage study involving the 7 families to be studied. Identification of causal gene variants would improve understanding of the pathophysiology of IA which may translate into more effective prevention and treatment. PUBLIC HEALTH RELEVANCE: Intracranial aneurysms (IAs) are small berry-like or balloon-like defects in the wall of a major intracranial artery and are associated with a mortality of 35-44% when they rupture. There is strong evidence for a genetic basis for IAs but specific gene variations causing IA have not been identified. By performing detailed analysis of gene variation in families with a large number of affected individuals, gene variations which are important in the formation and rupture of IA may be identified. The preliminary written comments of the reviewers are reproduced below. These comments were prepared prior to the meeting and may not have been edited after the full committee discussion of your application.